p,p'-Dichlorodiphenyltrichloroethane (DDT) (CASRN 50-29-3)

Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data, as outlined in the IRIS assessment development process. Sections I (Health Hazard Assessments for Noncarcinogenic Effects) and II (Carcinogenicity Assessment for Lifetime Exposure) present the conclusions that were reached during the assessment development process. Supporting information and explanations of the methods used to derive the values given in IRIS are provided in the guidance documents located on the IRIS website.

STATUS OF DATA FOR DDT

File First On-Line 03/31/1987

Category (section)

Status

Last Revised

Oral RfD Assessment (I.A.)

on-line

02/01/1996

Inhalation RfC Assessment (I.B.)

no data

Carcinogenicity Assessment (II.)

on-line

05/01/1991

_I.
Chronic Health Hazard Assessments for Noncarcinogenic Effects

_IA
Reference Dose for Chronic Oral Exposure (RfD)

The oral Reference Dose (RfD) is based on the assumption that thresholds
exist for certain toxic effects such as cellular necrosis. It is expressed
in units of mg/kg-day. In general, the RfD is an estimate (with uncertainty
spanning perhaps an order of magnitude) of a daily exposure to the human
population (including sensitive subgroups) that is likely to be without
an appreciable risk of deleterious effects during a lifetime. Please refer
to the Background Document for an elaboration of these concepts. RfDs
can also be derived for the noncarcinogenic health effects of substances
that are also carcinogens. Therefore, it is essential to refer to other
sources of information concerning the carcinogenicity of this substance.
If the US EPA has evaluated this substance for potential human carcinogenicity,
a summary of that evaluation will be contained in Section II of this file.

Weanling rats (25/sex/group) were fed commercial DDT (81%
P,P isomer and 19% O,P isomer) at levels of 0, 1, 5, 10 or 50 ppm for
15-27 weeks. The diet was prepared by mixing appropriate amounts of DDT
in corn oil solution with powdered chow. No interference with growth was
noted at any level. Females stored more DDT in peripheral fat than did
males, but pathologic changes were seen to a greater degree in males.
Increasing hepatocellular hypertrophy, especially centrilobularly, increased
cytoplasmic oxyphilia, and peripheral basophilic cytoplasmic granules
(based on H and E paraffin sections) were observed at dose levels of 5
ppm and above. The effect was minimal at 5 ppm (LOAEL) and more pronounced
at higher doses. No effects were reported at 1 ppm, the NOEL level used
as the basis for the RfD calculation. The authors believe the effect seen
at 5 ppm "represents the smallest detectable morphologic effect, based
on extensive observations of the rat liver as affected by a variety of
chemicals."

DDT fed to rats for 2 years (Fitzhugh, 1948) caused liver
lesions at all dose levels (10-800 ppm of diet). A LOAEL of 0.5 mg/kg
bw/day was established. Application of a factor of 10 each for uncertainty
of estimating a NOEL from a LOAEL, as well as for interspecies conversion
and protection of sensitive human subpopulations (1000 total) results
in the same RfD level as that calculated from the critical study. DDT-induced
liver effects were observed in mice, hamsters and dogs as well.

The Laug et al. (1950) study was chosen for the RfD calculation
because: 1) male rats appear to be the most sensitive animals to DDT exposure;
2) the study was of sufficient length to observe toxic effects; and 3)
several doses were administered in the diet over the range of the dose-response
curve. This study also established a LOAEL and a NOEL, with the LOAEL
(0.25 mg/kg/day) being the lowest of any observed for this compound.

__I.A.3.
Uncertainty and Modifying Factors (Oral RfD)

UF — A factor of 10 each was applied for the uncertainty
of interspecies conversion and to protect sensitive human subpopulations.
An uncertainty factor for subchronic to chronic conversion was not included
because of the corroborating chronic study in the database.

MF —None

__I.A.4.
Additional Studies/Comments (Oral RfD)

In one 3-generation rat reproduction study (Treon and
Cleveland, 1955), offspring mortality increased at all dose levels, the
lowest of which corresponds to about 0.2 mg/kg bw/day. Three other reproduction
studies (rat and mouse) show no reproductive effects at much higher dose
levels.

__I.A.5.
Confidence in the Oral RfD

Study — Medium
Database — Medium
RfD — Medium

The principal study appears to be adequate, but of shorter
duration than that desired; therefore, confidence in the study can be
considered medium to low. The database is only moderately supportive
of both the critical effect and the magnitude, and lacks a clear NOEL
for reproductive effects; therefore, confidence in the database can also
be considered medium to low. Medium to low confidence in the RfD follows.

__I.A.6.
EPA Documentation and Review of the Oral RfD

Source Document — This assessment is not presented in
any existing U.S. EPA document.

Other EPA Documentation — None

Agency Work Group Review — 12/18/1985

Verification Date — 12/18/1985

Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for p,p'-Dichlorodiphenyltrichloroethane conducted in September 2002 identified one or more significant new studies. IRIS users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or (202)566-1676.

__I.A.7.
EPA Contacts (Oral RfD)

Please contact the IRIS Hotline for all questions
concerning this assessment or IRIS, in general, at (202)566-1676 (phone),
(202)566-1749 (FAX) or hotline.iris@epa.gov
(internet address).

_II.
Carcinogenicity Assessment for Lifetime Exposure

Section II provides information on three aspects of the
carcinogenic assessment for the substance in question; the weight-of-evidence
judgment of the likelihood that the substance is a human carcinogen, and
quantitative estimates of risk from oral exposure and from inhalation
exposure. The quantitative risk estimates are presented in three ways.
The slope factor is the result of application of a low-dose extrapolation
procedure and is presented as the risk per (mg/kg)/day. The unit risk
is the quantitative estimate in terms of either risk per ug/L drinking
water or risk per ug/cu.m air breathed. The third form in which risk is
presented is a drinking water or air concentration providing cancer risks
of 1 in 10,000, 1 in 100,000 or 1 in 1,000,000. The rationale and methods
used to develop the carcinogenicity information in IRIS are described
in The Risk Assessment Guidelines of 1986 (EPA/600/8-87/045) and in the
IRIS Background Document. IRIS summaries developed since the publication
of EPA's more recent Proposed Guidelines for Carcinogen Risk Assessment
also utilize those Guidelines where indicated (Federal Register 61(79):17960-18011,
April 23, 1996). Users are referred to Section I of this IRIS file for
information on long-term toxic effects other than carcinogenicity.

_II.A.
Evidence for Human Carcinogenicity

__II.A.1.
Weight-of-Evidence Characterization

Classification — B2; probable human carcinogen.

Basis — Observation of tumors (generally of the liver)
in seven studies in various mouse strains and three studies in rats. DDT
is structurally similar to other probable carcinogens, such as DDD and
DDE.

__II.A.2.
Human Carcinogenicity Data

Inadequate. The existing epidemiological data are inadequate.
Autopsy studies relating tissue levels of DDT to cancer incidence have
yielded conflicting results. Three studies reported that tissue levels
of DDT and DDE were higher in cancer victims than in those dying of other
diseases (Casarett et al., 1968; Dacre and Jennings, 1970; Wasserman et
al., 1976). In other studies no such relationship was seen (Maier-Bode,
1960; Robinson et al., 1965; Hoffman et al., 1967). Studies of occupationally
exposed workers and volunteers have been of insufficient duration to be
useful in assessment of the carcinogenicity of DDT to humans.

__II.A.3.
Animal Carcinogenicity Data

Sufficient. Twenty-five animal carcinogenicity assays
have been reviewed for DDT. Nine feeding studies, including two multigenerational
studies, have been conducted in the following mouse strains: BALB/C, CF-1,
A strain, Swiss/Bombay and (C57B1)x(C3HxAkR). Only one of these studies,
conducted for 78 weeks, showed no indication of DDT tumorigenicity (NCI,
1978). Both hepatocellular adenomas and carcinomas were observed in six
mouse liver tumor studies (Walker et al., 1973; Thorpe and Walker, 1973;
Kashyap et al., 1977; Innes et al., 1969; Terracini et al., 1973; Turusov
et al., 1973). Both benign and malignant lung tumors were observed in
two studies wherein mice were exposed both in utero and throughout their
lifetime (Shabad et al., 1973; Tarjan and Kemeny, 1969). Doses producing
increased tumor incidence ranged from 0.15-37.5 mg/kg/day.

Three studies using Wistar, MRC Porton and Osborne-Mendel
rats and doses from 25-40 mg/kg/day produced increased incidence of benign
liver tumors (Rossi et al., 1977; Cabral et al., 1982; Fitzhugh and Nelson,
1946). Another study wherein Osborne-Mendel rats were exposed in this
dietary dose range for 78 weeks was negative (NCI, 1978) as were three
additional assays in which lower doses were given.

Tests of DDT in hamsters have not resulted in increased
tumor incidence. Unlike mice and humans, hamsters accumulate DDT in tissue
but do not metabolize it to DDD or DDE. Studies of DDT in dogs (Lehman,
1951, 1965) and monkeys (Adamson and Sieber, 1979, 1983) have not shown
a carcinogenic effect. However, the length of these studies (approximately
30% of the animals' lifetimes) was insufficient to assess the carcinogenicity
of DDT. DDT has been shown to produce hepatomas in trout (Halver, 1967).

DDT has produced both negative and positive responses
in tests for genotoxicity. Positive responses have been noted in V79 mutation
assays, for chromosome aberrations in cultured human lymphocytes, and
for sister chromatid exchanges in V79 and CHO cells (Bradley et al., 1981;
Rabello et al., 1975; Preston et al., 1981; Ray-Chaudhuri et al., 1982).
In one study, DDT was reported to interact directly with DNA; this result
was not confirmed in the absence of a metabolizing system (Kubinski et
al., 1981; Griffin and Hill, 1978).

DDT is structurally related to the following chemicals
which produce liver tumors in mice: DDE, DDD, dicofol and chlorobenzilate.

__II.B.3.
Additional Comments (Carcinogenicity, Oral Exposure)

The estimate of the slope factor did not
increase in the multigeneration feeding studies (Terracini et al., 1973;
Turusov et al., 1973) but remained the same from generation to generation.
A geometric mean of the above slope factors was used for the overall slope
factor of 3.4E-1. This was done in order to avoid excluding relevant data
(note that the appropriateness of this procedure is currently under study
by U.S. EPA). All tumors were of the liver; there were no metastases.
A few malignancies were observed in the Turusov study; possible neoplasms
were indicated in the Terracini and Tomatis studies. The Turusov study
was carried out over six generations, the Terracini assay for two. The
slope factor derived from data of Tarjan and Kemeny (1969) was not included
in the calculation of the geometric mean because the tumors developed
at different sites than in any other studies. In addition, there was a
problem in this study with possible DDT contamination of the feed.

DDT is known to be absorbed by humans in direct proportion
to dietary exposure; t(1/2) for clearance is 10-20 years.

The unit risk should not be used if the water concentration
exceeds 1E+3 ug/L, since above this concentration the unit risk may not
be appropriate.

__II.B.4.
Discussion of Confidence (Carcinogenicity, Oral Exposure)

Ten slope factors derived from six studies
were within a 13-fold range. The slope factor derived from the mouse data
alone was 4.8E-1 while that derived from the rat data alone was 1.5E-1.
There was no apparent difference in slope factor as a function of sex
of the animals. The geometric mean of the slope factors from the mouse
and rat data combined was identical for the same tumor site as that for
DDE [3.4E-1 per (mg/kg)/day], a structural analog.

__II.D.1.
EPA Documentation

The U.S. EPA risk assessment document
on DDT is an internal report and has not received external review.

__II.D.2.
EPA Review (Carcinogenicity Assessment)

Agency Work Group Review — 10/29/1986,
11/12/1986, 06/24/1987

Verification Date — 06/24/1987

Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the cancer assessment for p,p'-Dichlorodiphenyltrichloroethane conducted in September 2002 identified one or more significant new studies. IRIS users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or (202)566-1676.

__II.D.3.
EPA Contacts (Carcinogenicity Assessment)

Please contact the IRIS Hotline
for all questions concerning this assessment or IRIS, in general, at (202)566-1676
(phone), (202)566-1749 (FAX) or hotline.iris@epa.gov
(internet address).

Hilpert, D., W. Romen and H-G. Neumann. 1983. The role
of partial hepatectomy and of promoters in the formation of tumors in
non-target tissues of trans-4-acetylaminostilbene in rats. Carcinogenesis.
4(12): 1519-1525.

Drinking Water Health Advisories, EPA
Regulatory Actions, and Supplementary Data were removed from IRIS
on or before April 1997. IRIS users were directed to the appropriate
EPA Program Offices for this information.